Butorphanol tartrate (I), is chemically known as N-cyclobutylmethyl-3,14-dihydroxymorphinan tartrate, which is a morphinan-type synthetic opioid analgesic of phenanthrene series and is highly effective for the treatment of both chronic and acute pain. Parenterally administered Butorphanol tartrate is more potent than morphine and most other morphine analogs. Parenteral formulations of Butorphanol tartrate and its use for the relief of acute and chronic pain are first disclosed in the U.S. Pat. No. 3,775,414 (hereinafter referred to as '414) and U.S. Pat. No. 3,819,635 (hereinafter referred to as '635). A parenteral formulation of Butorphanol tartrate is commercially available under the name Stadol® from Bristol-Myers Laboratories, Inc. The chemical structure of Butorphanol tartrate (I) is depicted below:

The preparations of 14-hydroxymorphinan derivatives are schematically presented in scheme (1) and are disclosed in the aforesaid U.S. Pat. No. '414. The scheme (1) consists of the condensation of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone with 1,4 dibromobutane by means of sodium hydride (NaH) in benzene gives 3,4-dihydro-7-methoxy-2,2-tetramethylene-1(2H)-naphthalenone, which is treated with acetonitrile and n-butyllithium in tetrahydrofuran (THF) yielding1-hydroxy-7-methoxy-1,2,3,4-tetrahydro-2,2-tetramethylene- 1-naphthaleneacetonitrile. This compound is reduced with lithium aluminium hydride (LAH or LiAlH4) in THF to afford hydro-2,2-tetramethylene-1-naphthol and isomerized to 4a-(2-aminoethyl)-1,2,3,4,4a,9-hexahydro-6-methoxy-phenantrene. This amine is cyclized by reaction with bromine in chloroform (CHCl3) giving 3-methoxy-9a-bromonrhasybanan hydrobromide and isomerized with dehydrobromination by treatment with sodium bicarbonate (NaHCO3) in N,N-Dimethylformamide (DMF) affording 3-methoxy-DELTA(8,14)-morphinan. Further acetylation with trifluoroacetic anhydride yields 3-methoxy-N-trifluoroacetyl-DELTA(8,14)-morphinan, which is epoxidized with m-chloroperbenzoic acid (m-CPBA) in dichloromethane (DCM) giving 8,14-epoxy-3-methoxy-N-trifluoroacetylmorphina, which is further treated with sodium borohydride (NaBH4) in ethanol gives 8,14-epoxy-3-methoxymorphinan as an oily product that is treated with LiAlH4 in THF to open the epoxide ring and yield 14-hydroxy-3-methoxymorphinan. The condensation of 14-hydroxy-3-methoxymorphinan with cyclobutylcarbonyl chloride by means of pyridine in DCM affords N-cyclobutylcarbonyl-14-hydroxy-3-methoxymorphinan, which is reduced with LiAlH4 in refluxing THF giving N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan. Finally, it is demethylated by treatment with refluxing 48% hydrogen bromide (HBr) to provide N-cyclobutylmethyl-3,14-dihydroxymorphinan.

The process disclosed in U.S. Pat. No. '414 involves the use of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone compound as the starting material which undergoes a series of reaction steps to finally form Butorphanol, whereas the starting material used in the process involved in the present invention the reaction of 4-methoxyphenylacetic acid with 2-(1-cyclohexenyl)ethylamine compound leads to formation of Butorphanol and its salt via novel intermediates. Moreover, the process in the U.S. Pat. No. '414 does not discloses anywhere the formation of tartrate salt of Butorphanol.
The Butorphanol may also be prepared by another alternative synthetic procedure described in the said U.S. Pat. No. '635 by Bristol-MyersCompany. The procedure of said U.S. Pat. No. '635 schematically presented in scheme (2) is depicted below:

Thus, from the above scheme, it can be noted that U.S. Pat. No. '635 discloses the process for the preparation of Butorphanol involving the use of 7-methoxy-3,4-dihydro-1(2H)-naphthalenone compound as starting material which undergoes series of reaction steps to form Butorphanol. Whereas in the process of the present invention involves the use of 4-methoxyphenylacetic acid and 2-(1-cyclohexenyl)ethylamine to finally forms Butorphanol. It is to be noted that the starting material used in the process disclosed in U.S. Pat. No. '635 is expensive, whereas the starting material used in the present invention are economically and commercially available. The said US patents '414 and '635 discloses mixtures of isomers at all stages and involves costly last-step resolution, which is a major disadvantage. The present invention overcome this disadvantage by providing an economic method with increased yield and purity.
Onda et al, (Chem. Pharm. Bull. 1973; 21, 2359-2365) reported the epoxidation of 1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline to produce the following two epimeric epoxides;
and the diols resulting there from having the following intermediates,

Nothing in this paper describes, anticipates or teaches the preparation of the 9,10-diols in which the N-methyl is alkanoyl. The prior art has certain disadvantage and the present invention provides a novel process to synthesize 14-hydroxymorphinans via novel epoxide intermediate with surprisingly better results which overcome the disadvantage of the prior art.
Schnider and Hellerback (Helv. Chim. Acta., 1951; 34, 2218-2222) describes the preparation of morphinan from the same starting materials as used in the instant invention.
Schnider, Brossi and Vogler (Helv. Chim. Acta., 1954; 37, 710-720) further describes the preparation of 14-deoxymorphinans from the same starting materials as used in the instant invention.
Schnider and Hellerback (Helv. Chim. Acta., 1950; 33, 1437-1448) describes the preparation of 14-deoxymorphinans from the same starting materials as used in the instant invention. These prior arts do not link or suggest that 14-hydroxymorphinans could be prepared via this route.
U.S. Pat. No. 3,919,237discloses the cyclization of following compounds and the derivatives thereof into is morphinans and morphinan using boron trifluoride and a proton/hydronium ion donor as the cyclization catalyst. None of the compounds so produced have a 14-hydroxy substituent.

U.S. Pat. No. 4,052,389 discloses the protection of racemic 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro-isoquinoline using trifluoroacetic anhydride or ethyl formate or methyl chloroformate, whereas in present invention 1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro-isoquinoline was resolved with mandelic acid and further protected with di-tert-butyl dicarbonate (BOC anhydride) which is different from process involved in the said US '389 patent. The procedure of this patent is schematically presented in scheme (3) is depicted below:

The process disclosed in U.S. Pat. No. 4,115,389 (hereinafter referred to as U.S. Pat. No. '389) involves the use of dl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline compound as the starting material, which protected with cyclobutylcarbonyl chloride in DCM gives (±)-2-cyclobutylcarbonyl-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline, which further epoxidized with m-chloroperbenzoic acid in DCM yielding (±)-2-cyclobutylcarbonyl-9,10-epoxy-1 -(p-methoxybenzyl)-perhydroisoquinolines. This compound is treated with 15% aq. perchloric acid in THF to yield (±)-2-cyclobutylcarbonyl-9,10-dihydroxy-1-(p-methoxybenzyl)-perhydroisoquinoline. This compound is reduced with LiAlH4 in THF to afford (±)-2-cyclobutylmethyl-9,10-dihydroxy-1-(p-methoxybenzyl)-perhydroisoquinoline and is cyclized by reacting with borane solution in THF and phosphoric acid (H3PO4) giving (±)-N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan. This compound undergoes demethylation with 48% HBr solution to yield Butorphanol, whereas the starting material used in the process involved in the present invention the protection of (S)-1-(4-methoxy-benzyl)-1,2,3,4,5,6,7,8-octahydro-isoquinoline with boc anhydride which finally leads to formation of Butorphanol and its salt via novel intermediates. The use of LiAlH4 is industrially not viable, moreover the process disclosed in U.S. Pat. No. '389 is cumbersome and hence unscalable. The procedure of this patent schematically presented in scheme (4) is depicted below:

The procedure of U.S. Pat. No. 2,634,292 (hereinafter referred to as U.S. Pat. No. '292) and U.S. Pat. No. 2,634,273 (hereinafter referred to as U.S. Pat. No. '273) are schematically presented in scheme (5) is depicted below:

From the scheme (5) it can be noted that the process disclosed by U.S. Pat. No. '273 involves the reaction of cyclohexene-(1)-yl-ethylamine with phenylacetic acid to form corresponding phenyl acetic acid (cyclohexenyl-ethyl) amide. However, this process proceeds through different intermediates and this patent does not suggest the use of this process for butorphanol. The present invention differs from the process set out in scheme 5 by the use of novel intermediate and use of the said process to obtain butorphanol. Hence, there is no suitable process in the prior art for synthesis of butorphenol with high yield and purity and in economic manner. Therefore, there is a need for an economic process for the synthesis of butorphenol in high yield and purity.